(E)-3-(3-Bromo-phenyl)-N-isopropyl-2-(4-methanesulfonyl-phenyl)-acrylamide | 346629-94-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (E)-3-(3-Bromo-phenyl)-N-isopropyl-2-(4-methanesulfonyl-phenyl)-acrylamide
• 英文别名: (E)-N-isopropyl-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide；(E)-3-(3-bromophenyl)-2-(4-methylsulfonylphenyl)-N-propan-2-ylprop-2-enamide
• CAS: 346629-94-5
• 化学式: C₁₉H₂₀BrNO₃S
• 分子量: 422.343
• InChiKey: XNXWAICSXAKSPA-LDADJPATSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  71.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (E)-3-(3-Bromo-phenyl)-N-isopropyl-2-(4-methanesulfonyl-phenyl)-acrylamide 、 联硼酸频那醇酯 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride potassium acetate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (E)-N-Isopropyl-2-(4-methanesulfonyl-phenyl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acrylamide
  参考文献：
  名称：

  Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: Structure–activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor

  摘要：

  The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC50 < 1 nM) and also of LPS-induced TNF-alpha release in human whole blood (IC50 < 0.5 mu M). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC50 < 0.1 mg/kg ip) but require a dose of about 10 mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.08.036
• 作为产物：
  描述：

  (E)-3-(3-Bromo-phenyl)-2-(4-methanesulfonyl-phenyl)-acryloyl chloride 、 异丙胺 生成 (E)-3-(3-Bromo-phenyl)-N-isopropyl-2-(4-methanesulfonyl-phenyl)-acrylamide
  参考文献：
  名称：

  Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: Structure–activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor

  摘要：

  The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC50 < 1 nM) and also of LPS-induced TNF-alpha release in human whole blood (IC50 < 0.5 mu M). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC50 < 0.1 mg/kg ip) but require a dose of about 10 mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.08.036

文献信息

• Substituted 8-arylquinoline phosphodiesterase-4 inhibitors
  申请人：——

  公开号：US20020143032A1

  公开（公告）日：2002-10-03

  Novel sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, hydrochloride acid, or benzenesulfonic acid salts of substituted 8-arylquinolines, wherein the aryl group at the 8-position contains a substituent substituted-alkenyl group, are PDE4 inhibitors.

  新型硫酸、甲磺酸、对甲苯磺酸、2-萘磺酸、盐酸或苯磺酸盐的取代8-芳基喹啉，其中8位的芳基基团包含一个取代烯丙基基团，是PDE4抑制剂。
• [EN] SUBSTITUTED 8-ARYLQUINOLINE PHOSPHODIESTERASE-4 INHIBITORS<br/>[FR] INHIBITEURS DE 8-ARYLQUINOLINE PHOSPHODIESTERASE-4 SUBSTITUEE
  申请人：MERCK FROSST CANADA INC

  公开号：WO2001046151A1

  公开（公告）日：2001-06-28

  Novel substituted 8-arylquinolines represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein S1, S2 and S3 are independently H, -OH; halogen, -C1-C6alkyl, -NO2, -CN, or -C1-C6alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; R1 is a H, OH, halogen, carbonyl, or -C1-C6alkyl, -cycloC3-C6alkyl, -C1-C6alkenyl, -C1-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C1-C6alkylamino, -(C1-C6alkyl)(C1-C6alkyl)amino, -C1-C6alkyl(oxy)C1-C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl), -SOnNH(C1-C6alkyl), -C(O)N(C0-C6alkyl) (C0-C6alkyl), -NH-SOn-(C1-C6alkyl), -SOn-(C1-C6alkyl), -(C1-C6alkyl)-O-C(CN)-dialkylamino, or -(C1-C6alkyl)-SOn-(C1-C6alkal) group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C1-C6alkyl, -cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(C0-C6alkyl), -C(O)-aryloxy, -C1-C6alkoxy, -(C0-C6alkyl)(C0-C6alkyl)amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SOn-(C1-C6alkyl); A is CH, C-ester, or C-R4; R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -C1-C6alkyl, heterocycloC3-6alkyl, -C1-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -C1-C6alkyl)-SOn-(C1-C6alkyl), -C(O)N(C0-C6alkyl)(C0-C6alkyl), or -C1-C6alkylacylamino group, wherein any of the groups is optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C1-C6alkyl, -SOn-(C1-C6alkyl), -SOn-(aryl), aryloxy, -heteroaryloxy, C1-C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(C0-C6alkyl)(C0-C6alkyl)amino, -C(O)-N(C0-C6alkyl)(C0-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C1-C6alkoxy, -C1-C6alkyl, -cycloC3-C6alkyl, aryloxy, -C(O)OH, -C(O)O(C1-C6alkyl), halogen, -NO2, -CN, -SOn-(C1-C6alkyl), or -C(O)-N(C0-C6alkyl)(C0-C6alkyl); one of R2 and R3 must be an aryl or heteroaryl, optionally substituted; when R2 and R3 are both an aryl or heteroaryl, then R2 and R3 may be optionally connected by a thio, oxy, or (C1-C4alkyl) bridge to form a fused three ring system; are PDE4 inhibitors.

  代表公式（I）的取代的8-芳基喹啉新型化合物，或其药学上可接受的盐，其中S1、S2和S3独立选择为H、-OH、卤素、-C1-C6烷基、-NO2、-CN或-C1-C6烷氧基，其中烷基和烷氧基可以选用1-5个取代基，其中每个取代基独立选择为卤素或-OH；R1为H、OH、卤素、羰基或-C1-C6烷基、-环C3-C6烷基、-C1-C6烯基、-C1-C6烷氧基、芳基、杂环芳基、-CN、-杂环C3-C6烷基、-氨基、-C1-C6烷基氨基、-(C1-C6烷基)(C1-C6烷基)氨基、-C1-C6烷基（氧）C1-C6烷基、-C（O）NH（芳基）、-C（O）NH（杂环芳基）、-SOnNH（芳基）、-SOnNH（杂环芳基）、-SOnNH（C1-C6烷基）、-C（O）N（C0-C6烷基）（C0-C6烷基）、-NH-SOn-（C1-C6烷基）、-SOn-（C1-C6烷基）、-(C1-C6烷基)-O-C（CN）-二烷基氨基或-(C1-C6烷基)-SOn-(C1-C6烷基）基团，其中任何基团可以选用1-5个取代基，其中每个取代基独立选择为卤素、-OH、-CN、-C1-C6烷基、-环C3-C6烷基、-C（O）（杂环C3-C6烷基）、-C（O）-O-（C0-C6烷基）、-C（O）-芳氧基、-C1-C6烷氧基、-(C0-C6烷基)(C0-C6烷基)氨基、环烷氧基、酰基、酰氧基、-环C3-C6烷基、杂环C3-C6烷基、芳基、杂环芳基、羰基、氨基甲酰基或-SOn-（C1-C6烷基）；A为CH、C-酯或C-R4；R2和R3独立选择为芳基、杂环芳基、H、卤素、-CN、-C1-C6烷基、杂环C3-6烷基、-C1-C6烷氧基、羰基、氨基甲酰基、-C1-C6烷基-SOn-(C1-C6烷基)、-C（O）N（C0-C6烷基）（C0-C6烷基）或-C1-C6烷基酰胺基团，其中任何基团可以选用1-5个取代基，其中每个取代基独立选择为芳基、杂环芳基、卤素、- 、-C（O）OH、羰基、-CN、-C1-C6烷基、-SOn-(C1-C6烷基)、-SOn-(芳基)、芳氧基、-杂环芳氧基、C1-C6烷氧基、N-氧化物、-C（O）-杂环C3-C6烷基、-NH-环C3-C6烷基、氨基、-OH或-(C0-C6烷基)(C0-C6烷基)氨基、-C（O）-N（C0-C6烷基）（C0-C6烷基）取代基团，其中每个取代基团独立选择为-OH、C1-C6烷氧基、-C1-C6烷基、-环C3-C6烷基、芳氧基、-C（O）OH、-C（O）O（C1-C6烷基）、卤素、- 、-CN、-SOn-(C1-C6烷基)或-C（O）-N（C0-C6烷基）（C0-C6烷基），其中每个取代基团独立可以选用-OH、C1-C6烷氧基、-C1-C6烷基、-环C3-C6烷基、芳氧基、-C（O）OH、-C（O）O（C1-C6烷基）、卤素、- 、-CN、-SOn-(C1-C6烷基）或-C（O）-N（C0-C6烷基）（C0-C6烷基），其中R2和R3中的一个必须是芳基或杂环芳基，可以选用取代基，当R2和R3都是芳基或杂环芳基时，R2和R3可以选择通过硫、氧或（C1-C4烷基）桥连接而成为融合的三环系统；本化合物为PDE4抑制剂。
• [EN] SUBSTITUTED 8-ARYLQUINOLINE PHOSPHODIESTERASE-4 INHIBITORS<br/>[FR] ARYLQUINOLINES A SUBSTITUTION EN 8 TENANT LIEU D'INHIBITEURS DE PHOSPHODIESTERASE-4
  申请人：MERCK & CO INC

  公开号：WO2002069970A1

  公开（公告）日：2002-09-12

  Novel sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, hydrochloride acid, or benzenesulfonic acid salts of substituted 8-arylquinolines, wherein the aryl group at the 8-position contains a substituent substituted-alkenyl group, are PDE4 inhibitors.

  新型硫酸、甲烷磺酸、对甲苯磺酸、2-萘磺酸、盐酸或苯磺酸盐的取代8-芳基喹啉，其中8位上的芳基基团含有取代烯基基团，是PDE4抑制剂。
• [EN] SUBSTITUTED 8-ARYLQUINOLINE PDE4 INHIBITORS<br/>[FR] ARYLQUINONES INHIBITEURS DE PDE4 A SUBSTITUTION EN POSITION 8
  申请人：MERCK FROSST CANADA INC

  公开号：WO2003002118A1

  公开（公告）日：2003-01-09

  8-arylquinolines of formula(I) wherein the aryl group at the 8-position contains a meta two atom bridge to an optionally substituted phenyl or pyridyl group, are PDE4 inhibitors useful to treat asthma, chronic bronchitis, chronic obstructive pulmonary disease, arthritis, respiratory distress syndrome, allergic rhinitis, neurogenic inflammation, pain, rheumatoid arthritis, and other diseases. R1-R7 and Ar are as in claim 1.

  公式(I)中的8-arylquinolines，其中8位的芳基基团含有一个与可选取代的苯基或吡啶基团形成的间位两原子桥，是PDE4抑制剂，可用于治疗哮喘、慢性支气管炎、慢性阻塞性肺疾病、关节炎、呼吸窘迫综合症、过敏性鼻炎、神经源性炎症、疼痛、类风湿性关节炎和其他疾病。其中R1-R7和Ar如权利要求1所述。
• Substituted 8-arylquinolune pde4 inhibitors
  申请人：——

  公开号：US20040162314A1

  公开（公告）日：2004-08-19

  8-arylquinolines of formula (I) wherein the aryl group at the 8-position contains a meta two atom bridge to an optionally substituted phenyl or pyridyl group, are PDE4 inhibitors useful to treat asthma, chronic bronchitis, chronic obstructive pulmonary disease, arthritis, respiratory distress syndrome, allergic rhinitis, neurogenic inflammation, pain, rheumatoid arthritis, and other diseases. R 1 -R 7 and Ar are as in claim 1. 1

  公式(I)中的8-芳基喹啉，其中8位处的芳基团含有与可选取代苯基或吡啶基相连接的间位两个原子桥，是PDE4抑制剂，可用于治疗哮喘、慢性支气管炎、慢性阻塞性肺病、关节炎、呼吸窘迫综合症、过敏性鼻炎、神经源性炎症、疼痛、类风湿性关节炎和其他疾病。其中R1-R7和Ar如权利要求1.1所述。